Renal cell carcinoma (RCC) is the 12th most common cancer in
Ireland, accounting for about 3% of adult malignancies; the median
patient age at diagnosis is 65.[sup.1] There has been an increasing
incidence of RCC reported internationally, in part due to the increase
in incidentally diagnosed RCC[sup.2,3] as a result of the widespread use
and accuracy of modern imaging techniques, such as computed tomography
and magnetic resonance imaging.[sup.4,5]

Tumour-node-metastasis (TNM) staging, as well as pathological
nuclear (Fuhrman) grading system, has been identified as a reliable and
accurate prognosticator in RCC.[sup.6]-[sup.8] There have been reports
of a shift towards smaller renal tumours with an associated downwards
stage migration,[sup.9]-[sup.11] with an associated improved
cancer-specific survival.[sup.12] This stage migration towards smaller
lower stage tumours, however, was not observed in an Australian series;
an upward histological migration was demonstrated.[sup.13]

We assess the clinico-pathological features and survival of patients
with RCC in an Irish surgical cohort. Furthermore we evaluate whether a
stage migration has developed in our series over the study period.

Methods

A retrospective review of all nephrectomies (radical and partial)
performed in a single urology unit from 1995 to 2012 was conducted. Data
recorded included patient demographics, size of tumour, TNM
classification (adjusted according to the American Joint Committee on
Cancer [AJCC] 2010 guidelines), operative details and final pathology.
All specimens were analyzed in the same histopathology department by at
least 2 consultant histopathologists. All oncology cases were discussed
preoperatively and postoperatively at the departmental multidisciplinary
(urology, radiology, histopathology, medical oncology, radiation
oncology) conference. It is the policy of our ethics committee that no
consent or prior ethical approval is required for a retrospective chart
review.

The data was divided into 3 equal consecutive time periods for
comparison purposes: Group 1 for 1995 to 2000, Group 2 for 2001 to 2006
and Group 3 for 2007 to 2012.

All statistical analyses were performed using Minitab version 16.0
(Minitab Inc., State College PA). Differences in patient characteristics
between the 6 time periods were tested using Fisher's exact test
and one-way analysis of variance (ANOVA). Overall and disease-specific
survival was calculated using the Kaplan-Meier method. Time was
calculated from date of diagnosis to date of death or to 31 December
2012 if alive at that time. The log-rank test was used to test
differences in the disease-specific survival between the 6 periods. All
deaths were cross-referenced with the National Cancer Registry of
Ireland and the General Registry Office. A p value less than 0.05 was
considered statistically significant.

Results

Between 1995 and 2012, 507 patients underwent nephrectomy for RCC in
our unit. Overall, rates of nephrectomies increased over the study
period (Fig. 1).

There were 105 patients in Group 1 (1995-2000), 146 in Group 2
(2001-2006) and 256 in Group 3 (2007-2012). The median age was 60.1
(range: 23-88). There were 198 females and 309 males. No difference in
age (p = 0.275) or sex distribution (p = 0.871) was observed between the
groups. The clinico-pathological parameters are summarised in Table
1.

The median tumour size was 5.8 cm (range: 1.2-20) and there was no
statistical reduction in size observed over time (p=0.477). A total of
142 (28%) RCCs were classified as pT1a, 111 (21.9%) as pT1b, 67 (13.2%)
as pT2, 103 (20.3%) as pT3a, 75 (14.8%) as pT3b and 9 (1.8%) as pT4.
Organ-confined (pT1a, pT1b, pT2) tumours accounted for 63.1% of the
series and there was no statistical T-stage migration observed (p =
0.213). 6.5% were Fuhrman nuclear grade 1, 43.6% were grade 2, 38.3%
were grade 3 and 11.6% were grade 4. There was a significant grade
reduction over time (p = 0.017), with an increased representation of
grade 1 (from 1.9% to 6.3%) and grade 2 (from 35.2% to 55.6%) tumours
and a decrease in grade 3 (51.9% to 24.6%). The histological subtypes
remained consistent with time, with clear cell carcinomas being the most
common (83%), followed by papillary carcinomas (9.3%) and chrombophobe
carcinomas (5.9%).

In our Irish surgical series, we found an increase in the number of
nephrectomies performed over the study period, with a threefold increase
since 1995. Despite this, a migration towards lower T-stage tumours has
not been observed and mean tumour size has remained stable (6.44 cm). We
found that 63.1% represented organ-confined tumours (pT1a, pT1b, pT2)
and this has remained constant. We observed a trend towards lower
nuclear (Fuhrman) grade tumours, with an increasing representation of
grade 1 tumours and grade 2 tumours, and a decrease in grade 3 tumours.
The cause for a decreasing tumour grade is uncertain particularly given
that tumour size has remained consistent in our series. One contributing
factor may be that modern imaging is detecting tumours earlier. Also, it
may be a change in pathological reporting, which would need to be tested
by re-grading all specimens across the 3 groups - this is not
practical.

Our findings are not consistent with previous international reports.
A large analysis from the United States, reviewing 205 963 RCCs,
demonstrated a stage migration pattern; clinical (radiological based)
stage 1 RCC increased from about 43% to 57% in new patients between 1993
and 2004. A subset analysis of only surgically staged patients still
observed an increase in pathological pT1 RCC patients from 51% to 60%
between 1993 and 2004. There was a concomitant decrease in the
proportion of all other stages of disease during the same time
interval.[sup.9] Pathologic and clinical staging may yield different
results because tumours tend to be larger on imaging than their ultimate
size when measured pathologically.[sup.14] The size of stage 1 tumours
also decreased from a mean of 4.1 cm in 1993 to a mean of 3.6 cm in
2004. The mean tumour size is smaller than our series and may reflect
our purely surgically treated series (stage 1 tumour mean size 4.01 cm);
smaller tumours undergoing surveillance were not included in our
analysis.

Similarly, Pichler and colleagues reported a stage migration and
decrease in tumour size in a sizable central European Caucasian series.
The observed stage migration mainly consisted of an increasing number of
resections of pT1a (12.5% to 32.6%) tumours and a decreasing number of
pT3a (46.6% to 24.1%) tumours over the 25-year study period; there was
also an associated decrease in mean tumour size from 6.7 cm to 4.8
cm.[sup.10] This stage migration was accompanied by an improved
metastases free 5-year survival from 78.7% to 90.3%. This survival
benefit was based upon a cohort in whom no adjuvant or neo-adjuvant
therapies were used. This stage migration and shift towards smaller less
severe tumours were echoed in findings by Lyrdal and colleagues who
assessed Scandinavians from the Swedish Cancer Registry.[sup.11] Not
only did the authors assess clinically significant RCCs, they also
analyzed autopsy-detected RCCs. The frequency of autopsy-detected
tumours decreased from 24% to 7% indicating more incidentally diagnosed
RCCs. In contrast to these 3 large studies, Doeuk and colleagues
reported a similar-sized Australian series to our study population (n =
499). They found an upward stage shift with an increasing proportion of
stage 3 tumours from 13.9% to 21.5%. They also observed a trend towards
more aggressive Fuhrman grade 3 tumours 17.6% to 30.8%. Furthermore,
despite conventional (clear cell) carcinomas remaining the most common
histological subtype, there was a significant increased representation
of papillary carcinomas, which have a known poorer prognosis than clear
cell[sup.15,16] or chrombophobe.[sup.17]

A large review of the National Cancer Database assessed the
pathological characteristics of 47 909 RCCs. Most (66%) of these tumours
were organ confined and the mean size was 6.49 cm - similar to our
series. Pathological (AJCC) stage, nuclear (Fuhrman) grade and
histological subtype are key prognosticators in RCC.[sup.7,18] Our data
support the significant survival advantage with regard to T-stage,
nuclear grade and histological subtype. Management and risk algorithms
have been validated; these algorithms incorporate these parameters for
the stratification of patients with RCC (Memorial Sloan-Kettering Cancer
Centre RCC nomogram,[sup.19,20] The University of Los Angeles, (UCLA)
Integrated Staging System[sup.21] and the Mayo Clinic (Rochester, MN)
stage, size, grade and necrosis score (SSIGN).[sup.22]

The rising incidence of RCC, often accompanied by a fall in
mortality, has been well-described and attributed to an increase in
incidentally discovered renal tumours.[sup.23] Falebita and colleagues
reported that the incidence of RCC from 1994 to 2004 rose and it was
largely, but not entirely, due to an increase in incidentally diagnosed
cancers.[sup.24] The improved cancer-specific survival of incidental
cases has not, thus far, resulted in a decrease in overall mortality
from kidney cancer, perhaps because of this lead-time bias.[sup.25]

The most important limitation of our retrospective single centre
study was that we only reported patients who underwent nephrectomy. As a
result, we were not able to report incidence or prevalence of RCC given
that this was an analysis of a purely surgical series. In our study,
patients who were undergoing radiological surveillance for small
suspicious renal masses and those who underwent radiological
intervention may influencing factors as to why we did not observe the
reported migration towards smaller lower stage tumours. Furthermore the
adjustment of tumour stage to the AJCC 2010 guidelines was based on
histopathological reports. The number of patients in our series with
metastatic disease is quite small reflecting our survival rates;
therefore, many patients with metastatic disease would not have
undergone surgery and were therefore not included in this series.

Conclusion

Despite a threefold increase in the number of nephrectomies
performed over the study period, the previously reported stage migration
towards smaller tumours was not observed in our series. There was,
however, a significant grade reduction. Tumour stage, nuclear grade and
histological subtype are significant prognosticators of relative
survival in RCC.

The authors would like to acknowledge the help of the National
Cancer Registry of Ireland and the General Registry Office.